1. Field of the Invention
The present invention provides a composition of hyaluronic acids for treating and preventing mucosa related disorders or diseases whereas the symptoms include ulceration, inflammation, allergic reaction and bleeding.
2. Description of the Prior Arts
Hyaluronic acid, also known as hyaluronan, hyaluronate and sodium hyaluronate, is generally referred to as HA, which is a natural glycosaminoglycan macromolecule including disaccharides composed of the alternative N-acetyl-D-glucosamine and D-glucuronic acid linked via alternative β-1,3 and β-1,4 glycosidic bonds. HA found in nature with a molecular weight (Mw) between 50,000 Dalton (Da) and a few million Dalton usually has high viscosity.
HA found in nature is the fluid with elasticity, filling between the cells and the collagenous fibers and covering onto some epidermal tissues, mainly for protecting and lubricating cells, for providing a platform for transporting the regulatory T cell, and also for stabilizing collagen network and protecting collagen network from the mechanical damage. HA is also a major lubricant in the tendon and the tendon sheath and on the surface of the synovial membrane due to its lubricant feature and being a high shock absorber, and HA is helpful for the tissue rheological mechanics, motion and the cell proliferation (referring to Delpech, B. et al., 1997, Hyaluronan: fundamental principles and applications in cancer. J. Intern. Med. 242, 41-48), and participates in the receptor interaction on the surface of some cells, particularly to be the major receptor of CD44. CD44 is widely accepted as a marker of the activated lymphocyte (referring to Teder P, et al., 2002, Resolution of lung inflammation by CD44. Science, 296:155-158).
Recently, HA is applied in clinical treatment in the sodium salt form mainly in eye, skin, orthopedics, surgery, arthritis, artery treatment and in cosmetic fields. The HA with alkali metal ion, alkaline earth metal ion (for example the magnesium ion), aluminum ion, ammonium ion, and salt form of the replacement of the ammonium ion can be the carrier for assisting drug absorption (referring to Belgium Patent 904,547). The silver salt is used as the mycocide and the gold salt is used for treating the rheumatoid arthritis among the heavy metal salt of the HA (referring to WO 87/05517).
U.S. Pat. No. 5,888,986 discloses a method and related structure for using HA at an effective concentration to treat cystitis, wherein the average Mw of the HA is more than 200,000 Da. There is only one species of HA with a certain Mw been applied in the embodiment thereof. For example, HA with the average molecular weight of 650 kDa or 1,900 kDa is used to treat the cystitis; however, the single species of HA with the certain average molecular weight cannot be used for both prompt treatment and sustained effect. US patent application 2005/0080037 discloses the use of HA for treating acute and overuse sprain and the reaction thereof, wherein the Mw of the HA is only between 900 KDa and 1200 KDa, and the single species of HA with the certain average Mw cannot perform both prompt healing and prolonged action.
U.S. Pat. No. 7,354,910 discloses that the hyaluronic acid and hyaluronate with Mw between 600 KDa and 1,200 KDa can be applied to treat inflammatory bowel disease (IBD). However, hyaluronic acid and hyaluronate with merely one average molecular weight could not cover both the immediate and sustained functions in the treating effect after being injected into the patient, therefore, it is very inconvenient for patients clinically.
European patent 1369119 discloses the use of HA for treating autoimmune disease with HA with Mw of 0.6 MDa to 3 MDa. However, the referenced patent only uses one species of HA with a certain average molecular weight, lacking in both quick and long term effects simultaneously.
The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin, covered in epithelium, and involved in absorption (gastrointestinal tract) and secretion (gastrointestinal and respiratory tract). They line cavities that are exposed to the external environment and internal organs and contiguous with the skin at several body areas: at the nostrils, the mouth, the lips, the eyelids, the ears, the genital area, and the anus. The sticky, thick fluid secreted by the mucous membranes and glands is termed mucus. The term mucous membrane refers to where they are found in the body and not every mucous membrane secretes mucus.
Eye
Conjunctivitis refers to inflammation of the conjunctiva (the outermost layer of the eye and the inner surface of the eyelids). It is most commonly due to an infection or an allergic reaction (referring to Richards A, May 2010. “Conjunctivitis”. Pediatr Rev 31 (5): 196-208).
Ear
Otitis is a general term for inflammation or infection of the ear, in both humans and other animals. It is subdivided into: Otitis externa that involves the outer ear and ear canal; otitis media that involves the middle ear; otitis interna that involves the inner ear.
Allergic Rhinitis
Rhinitis is defined as inflammation of the nasal membranes and is characterized by a symptom complex that consists of any combination of the following: sneezing, nasal congestion, nasal itching, and rhinorrhea. The eyes, ears, sinuses, and throat can also be involved. Allergic rhinitis is the most common cause of rhinitis and affects approximately 20% of the population. While allergic rhinitis is not a life-threatening condition, complications can occur and the condition can significantly impair quality of life, which leads to a number of indirect costs (referring to Bousquet J et al. Allergic rhinitis management pocket reference 2008. Allergy 2008 August; 63 (8):990-996). US patent application 20050107330 discloses a pharmaceutical composition for curative topical treatment of rhinitis comprising at least one acidic glycosaminoglycan. However, this invention also contains at least one sympathomimetic suitable for topical application and having vasoconstrictor action or detumescent action on the mucous membrane or its physiologically acceptable salts or derivatives. Therefore, it did not disclose or teach combining HAs with two different average molecular weights.
Mouth
Oral mucosa is the mucous membrane epithelium of the mouth. An oral ulcer is an open sore inside the mouth, or, in rare cases, a break in the mucous membrane or the epithelium on the lips or surrounding the mouth. The types of ulcers are diverse, with a multitude of associated causes including: physical abrasion, acidic fruit, infection, other medical conditions, medications, and cancerous and nonspecific processes. Once formed, the ulcer may be maintained by inflammation and/or secondary infection. Two common types are aphthous ulcers (“canker sores”) and cold sores (fever blisters, oral herpes). Cold sores around the lip are caused by viruses (referring to J. M. Casiglia, et al., October 2006. “Aphthous stomatitis”. Emedecine (website)).
Bronchitis
Bronchitis is inflammation of the mucous membranes of the bronchi, the airways that carry airflow from the trachea into the lungs. Bronchitis can be divided into two categories, acute and chronic, each of which has unique etiologies, pathologies, and therapies. Acute bronchitis often occurs during the course of an acute viral illness such as the common cold or influenza. Chronic bronchitis most often develops due to recurrent injury to the airways caused by inhaled irritants. Cigarette smoking is the most common cause, followed by air pollution and occupational exposure to irritants (Cohen, Jonathan and William Powderly. Infectious Diseases. 2nd ed. Mosby (Elsevier), 2004. “Chapter 33: Bronchitis, Bronchiectasis, and Cystic Fibrosis”). US patent application 20030171332 discloses a method of treating respiratory conditions by a polysaccharide capable of binding CD44. However, only one single species of HA can be involved.
Gastrointestinal Mucosa
The mucosa is the innermost layer of the gastrointestinal wall that is surrounding the lumen, or open space within the tube. This layer comes in direct contact with food bolus, and is responsible for absorption, digestion, and secretion which are the important processes in digestion.
The mucosae are highly specialized in each organ of the gastrointestinal tract, facing a low pH in the stomach, absorbing a multitude of different substances in the small intestine, and also absorbing specific quantities of water in the large intestine. Reflecting the varying needs of these organs, the structure of the mucosa can consist of invaginations of secretory glands (e.g., gastric pits), or it can be folded in order to increase surface area.
The gastrointestinal mucosa forms a barrier between the body and a lumenal environment which not only contains nutrients, but is laden with potentially hostile microorganisms and toxins. The challenge is to allow efficient transport of nutrients across the epithelium while rigorously excluding passage of harmful molecules and organisms into the animal. The exclusionary properties of the gastric and intestinal mucosa are referred to as the “gastrointestinal barrier”. In general, toxins and microorganisms that are able to breach the single layer of epithelial cells have unimpeded access to the systemic circulation.
Gastroesophageal reflux disease (GERD) is chronic symptoms or mucosal damage caused by gastric acid coming up from the stomach into the esophagus. A typical symptom is heartburn. GERD is usually caused by changes in the barrier between the stomach and the esophagus, including abnormal relaxation of the lower esophageal sphincter, which normally holds the top of the stomach closed; impaired expulsion of gastric reflux from the esophagus, or a hiatal hernia. These changes may be permanent or temporary (“transient”) (referring to DeVault K R, 1999. “Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology”. Am J Gastroenterol 94 (6): 1434-42).
Peptic Ulcer
As generally known a peptic ulcer and also known as PUD or peptic ulcer disease, peptic ulcer is an ulcer (defined as mucosal erosions equal to or greater than 0.5 cm) of an area of the gastrointestinal tract that is usually acidic and thus causes extreme pain Almost 70-90% of ulcers are associated with Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach. Ulcers can also be caused or worsened by drugs such as aspirin, Plavix (clopidogrel), ibuprofen, and other NSAIDs (non-steroid anti-inflammatory drugs).
Contrary to general belief, peptic ulcers arise more in the duodenum (first part of the small intestine, just after the stomach) rather than in the stomach. About 4% of stomach ulcers are caused by a malignant tumor, so multiple biopsies are needed to exclude cancer. Duodenal ulcers are generally benign. The classification of peptic ulcer by region or location includes: Stomach (called gastric ulcer); Duodenum (called duodenal ulcer); Esophagus (called esophageal ulcer); Meckel's Diverticulum (called Meckel's Diverticulum ulcer).
The above embodiments all stand for mucosa related disorder or disease but are not limited to aforementioned. The disclosed disorders or diseases may be treated by different drugs or therapies so far. However, such treatments are mostly achieved by drug with complicated composition through highly specialized preparation processes and not by a simple and safe treatment. No prior art except the inventor of the present invention taught or predicted combining two species of HA with two different average molecular weights (LMWHA and HMWHA) separated by 1.5 million Da, which means a person skilled in the art cannot induce the concept of the utility of the mixture by combining any other prior arts.